Updated overall survival and final progression-free survival data for patients with treatment-naive advanced ALK-positive non-small-cell lung cancer in the ALEX study

Abstract

Background: The ALEX study demonstrated significantly improved progression-free survival (PFS) with alectinib versus crizotinib in treatment-naive ALK-positive non-small-cell lung cancer (NSCLC) at the primary data cut-off (9 February 2017). We report mature PFS (cut-off: 30 November 2018) and overall survival (OS) data up to 5 years (cut-off: 29 November 2019). Patients and methods: Patients with stage III/IV ALK-positive NSCLC were randomized to receive twice-daily alectinib 600 mg (n ¼ 152) or crizotinib 250 mg (n ¼ 151) until disease progression, toxicity, withdrawal or death. Primary end point: investigator-assessed PFS. Secondary end points included objective response rate, OS and safety. Results: Mature PFS data showed significantly prolonged investigator-assessed PFS with alectinib [hazard ratio (HR) 0.43, 95% confidence interval (CI) 0.32e0.58; median PFS 34.8 versus 10.9 months crizotinib]. Median duration of OS follow-up: 48.2 months alectinib, 23.3 months crizotinib. OS data remain immature (37% of events). Median OS was not reached with alectinib versus 57.4 months with crizotinib (stratified HR 0.67, 95% CI 0.46e0.98). The 5-year OS rate was 62.5% (95% CI 54.3e70.8) with alectinib and 45.5% (95% CI 33.6e57.4) with crizotinib, with 34.9% and 8.6% of patients still on study treatment, respectively. The OS benefit of alectinib was seen in patients with central nervous system metastases at baseline [HR 0.58 (95% CI 0.34e1.00)] and those without [HR 0.76 (95% CI 0.45 e1.26)]. Median treatment duration was longer with alectinib (28.1 versus 10.8 months), and no new safety signals were observed. Conclusions: Mature PFS data from ALEX confirmed significant improvement in PFS for alectinib over crizotinib in ALKpositive NSCLC. OS data remain immature, with a higher 5-year OS rate with alectinib versus crizotinib. This is the first global randomized study to show clinically meaningful improvement in OS for a next-generation tyrosine kinase inhibitor versus crizotinib in treatment-naive ALK-positive NSCLC. Clinical trials number: NCT02075840.

Targeted Therapy in Advanced and Metastatic Non-Small Cell Lung Cancer. An Update on Treatment of the Most Important Actionable Oncogenic Driver Alterations

“…PFS, the primary endpoint of the trial, was found to be significantly higher with alectinib compared to crizotinib (HR 0.47). Updated results confirmed the significant improvement in PFS [148]. Median PFS with alectinib was 34.8 months compared to 10.9 months with crizotinib.…”

Feasibility and Challenges for Sequential Treatments in ALK-Rearranged Non-Small-Cell Lung Cancer

“…The firstgeneration (1G) tyrosine kinase inhibitor (TKI) crizotinib was approved by the European Medicines Agency (EMA) already in August 2011, based on superior efficacy and tolerability compared to conventional chemotherapy (2). During the last two years, it was superseded by second-generation (2G) compounds in the upfront setting, especially alectinib and brigatinib, whose even better systemic and intracranial activity was reflected in longer-lasting responses and a median overall survival (OS) exceeding 5 years in the ALEX trial (3,4). More recently, the third-generation (3G) drug lorlatinib demonstrated even higher efficacy and is currently the standard option after failure of any next-generation ALK TKI (5,6).…”

“…More recently, the third-generation (3G) drug lorlatinib demonstrated even higher efficacy and is currently the standard option after failure of any next-generation ALK TKI (5,6). Accumulating evidence from real-world retrospective analyses as well as clinical trials underlines the importance of sequential TKI administration in order to optimize patient outcome (3,7,8). Indeed, newer compounds are more potent ALK inhibitors and show broader activity against ALK resistance mutations, therefore they can salvage patients failing older TKI (9).…”

Alectinib Treatment of ALK Positive Non Small Cell Lung Cancer Patients with Brain Metastases: Our Clinical Experience

“…Whole brain irradiation (WBI) and chemotherapy as a standard treatment in NSCLC patients with poor PS and BMs is of little clinical value. It offers median OS (overall survival) of approximately 3 months [9] in comparison with alectinib treatment, where median overall survival will not be reached in 5-years follow-up [10]. Indication for molecular based therapy for patients with NSCLC harboring corresponding target genes therefore should be determined separately from that for cytotoxic chemotherapy for non-selected population.…”

“…The cumulative incidence rate (CIR) of CNS progression in the ALEX ITT population, given the daunting risks of non-CNS progression and death, was 9.4 percent with alectinib versus 41.4 percent with crizotinib (26,27). Median OS was NR (Non Reachable) with alectinib and 57.4 months with crizotinib (95% CI 34.6-NR) (10). Based on the ALEX data, the National Comprehensive Cancer Network guidelines were updated to include alectinib as a category 1 recommendation for first-line treatment of ALK+ NSCLC patients.…”